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Chemotherapy or Radiotherapy for Reticuloses ?
1184
the persistence of cholinergic pathways. The loss of the peristaltic wave presumably results from disappearance of the myenteric ganglia of the body of the oesophagus.
Chemotherapy
explained by
.
How, then, are we to treat this disorder ? There can be no hope of return to normal function, and reduction of the resting tone of the sphincter seems the only possible method. Anticholinergic drugs have not
proved successful, although intravenoushyoscine butylbromide has been claimed to relax the sphincter .12 Dilatation, although easily performed, is unpredictable in its efficacy; only about half to two-thirds of patients obtain reasonable relief for long periods and then often only after several dilatations.13 14 With this procedure the risk of oesophageal rupture is about 2%.13 It cannot be carried out at all when the oesophagus is grossly dilated with sigmoid deformity; and where it can be carried out the greatest disadvantage perhaps is the danger of reducing symptoms to a level at which the patient will accept the disorder, unaware of the insidious progression towards stage 3. BRAIN1 believes that Heller’s cardiomyotomy is the treatment of choice, especially in the earlier stages, since fibrous strictures from foodstagnation oesophagitis and the development of carcinoma seem to be commoner in the large sigmoid oesophagus. BROWSE and CARTER,15 reviewing their experience of the late results of cardiomyotomy in 15 patients followed for from four to twelve years, conclude that Heller’s operation, though useful, achieves little. Only 7 patients were cured of their dysphagia, but 7 more felt it was much improved. 13 had no further regurgitation and felt that on this ground alone the operation was worth while. Pain was relieved by operation in 2 out of 5 cases. Radiological assessment after operation showed that 5 patients had no delay in emptying and no dilatation, while 9 had persistent obstruction and dilatation. No return of peristaltic activity was seen; but in about half the cases the oesophageal dilatation was considerably reduced-which seems to accord with the experience of other workers.16
Perhaps we expect more from cardiomyotomy than it can give. The most important aim of treatment should be to halt progression to stage 3. It seems likely that treatment by administration of nitrites is justifiable only while the patient is waiting for more vigorous treatment; they do not prevent progressive dilatation and are of little help in the earlier stages when the oesophagus can hold only a few ounces. Dilatation of the sphincter may be suitable during stage 1, provided that the extent of cesophageal dilatation is assessed radiologically least once a year; but the advent of stage 2 is an indication for operation,2 13which should never be delayed until stage 3. How many have said after cardiomyotomy, undertaken after temporising treatment with nitrites or dilatations: " Why ever didn’t you operate years ago ?" at
Wright, J. T. Brit. J. Radiol. 1961, 34, 113. Olsen, A. M., Harrington, S. W., Moersch, H. J., Andersen, H. A. J. thorac. Surg. 1951, 22, 164. 14. Lawrance, K., Shoesmith, J. H. Thorax, 1959, 14, 211. 15. Browse, N. L., Carter, S. J. Brit. J. Surg. 1961, 49, 59. 16. Acheson, E. D., Hadley, G. D. Brit. med. J. 1958, i, 549. 12. 13.
or
Radiotherapy
for Reticuloses ? LONG before any effective chemotherapy had been treatment of reticuloses by X rays and radium had become well established. Special hospitals for radiotherapy had been built, and a widespread service for diagnosis and follow-up had been organised. The radiotherapists had collected an impressive body of information about the sensitivity of tumours and reticuloses, the best methods of applying radiotherapy, and the likely survival of the patients. Chemotherapy for tumours and reticuloses is based on the properties of nitrogen mustard, and nearly all the drugs used today For tumours, radioare variations of this molecule. remains the best treatment in nearly all cases. therapy is used for Chemotherapy only palliation of tumours beyond the reach of radiotherapy or in special circumstances ; for instance, CLIFFORD et al.l showed what could be done in malignant disease of the head and neck by a combination of nitrogen-mustard therapy and auto-
introduced, the
logous marrow infusion: they used this method because X-ray therapy is not available in East Africa. In reticuloses, on the other hand, chemotherapy has advantages because the lesions are often multifocal and spread over various areas of the body. Radiotherapy is hardly ever used nowadays in chronic leukaemias: busulphan for chronic myeloid leukaemia, and mustine or chlorambucil for chronic lymphatic leukaemia, are the remedies of choice. But when the management of Hodgkin’s disease and the similar reticuloses is to be decided, the choice between chemotherapy and radiotherapy is much less clear-cut. The subject has been debated by the British Institute of Radiology. HOLME and KUNKLER2 present the case for radiotherapy. They admit that when a reticulosis has become widespread such treatment is no longer worth while; but " where the disease is apparently still localised to one lymph node area or to the site of origin and adjacent nodes, the survival rate following radiotherapy is of the same order as that obtained in carcinomata of accessible sites ". In a series of 48 patients with localised lymphosarcoma, the five-year survival-rate was 44%; for 86 patients with reticulosarcoma the rate was 30%. Adequate treatment has some drawbacks because not only the tumour has to be irradiated: the lymph-nodes draining the affected area and any probable line of extension from the primary area are also included. Thus, the irradiated area may extend " from the base of skull to below the clavicles-and doses of the order of 3,000r in four weeks must be given ". The side-effects of such treatment can include loss of taste and smell, reduction of salivary secretion, radiation caries, radiation myelitis, and late affection of lungs, kidneys, bowels, and bones. Nevertheless, HOLME and KUNKLER believe that the method is justified by the results: the five-year survival figure for lymphosarcoma and reticulosarcoma of the tonsil was 55%, and for similar affections of the cervical nodes 62%. The survival-rate for apparently localised cases of Hodgkin’s disease was 53%, and these workers note that 1. 2.
Clifford, P., Clift, R. A., Duff, J. K. Lancet, 1961, i, 687. Holme, G. M., Kunkler, P. B. Brit. J. Radiol. 1961, 34, 569.
1185
local
is rare so that supplementary chemois therapy unlikely to improve the result: they agree with EDITH PATERSON,3 who found no significant effect on prognosis when mustine was given simultaneously with
clinics where chemotherapy has for some time been given first in preference to radiotherapy: the figures for fouryear survival with proper clinical grading in a series of patients so treated would provide a basis for a proper
X-ray therapy.
comparison.
recurrence
HANCOCK4 states that in his hospital the practice is
to
generalised Hodgkin’s disease first with chemotherapy, using either intravenous mustine or oral chlorambucil or both, which is followed by radiotherapy to any residual masses. He cites the figures published by COOK5 of Michigan, who studied a group of 212 patients; about half of them had high-voltage X-ray therapy alone, and about half had X-ray and nitrogenmustard therapy combined. The five-year survivalrates of the two groups were about equal, but, since treat
of the more advanced cases received combined and the localised cases X-ray alone, COOK considers that combined treatment is the more effective. JELLIFFE and NABARRO6 report their experience with corticosteroids in the treatment of reticuloses. They recommend prednisone in doses of 30 mg. or more daily. On the whole their results were disappointing; but steroids are useful in haemolytic ansemia when this occurs, and in the reduction of gland masses when further radiotherapy or chemotherapy is inadvisable. No paper from this debate gives information about the results of chemotherapy alone. Many such reports have, of course, appeared 7; but it is difficult to compare the reported results of pure chemotherapy and chemotherapy combined with X-ray treatment, for two reasons. The first is that few accounts of chemotherapy give results for four-year or five-year survival, and in many cases the drug on trial has been given to patients who had already received other forms of treatment. For example, WALL and CONRAD s have reported their experience with cyclophosphamide; they treated 29 patients with Hodgkin’s disease, 28 of whom had previously received radiotherapy or chemotherapy or both; none of the patients were followed for more than a year. They reported " good " results in 10 patients on this short-term basis. The second reason is that few reporters give a clinical classification of the severity of their cases. WARWICK and SELLERS9 divided cases into class i (disease limited to a single area), class n (disease involving more than one lymphatic group in a single anatomical area [a] without and [b] with constitutional signs and symptoms), and class III (generalised disease with serious constitutional signs and symptoms). The prognosis, based on four-year survival, is about three times as good for class i as for class III, with class 11 intermediate. Unfortunately, the usual practice, when both forms of treatment are available, is to give radiotherapy to patients in class i and class lia, and to give chemotherapy to the more severely affected patients in classes lib and III. This bias makes objective comparison between the two forms of treatment difficult. There are
most
treatment
3. Paterson, E. Brit. J. Cancer, 1958, 12, 332. 4. Hancock, P. E. T. Brit. J. Radiol. 1961, 34, 573. 5. Cook, J. C. Amer. J. Roentgenol. 1959, 82, 651. 6. Jelliffe, A. M., Nabarro, J. D. N. Brit. J. Radiol. 1961, 34, 577. 7. See Lancet, 1959, i, 1233; ibid. 1961, i, 265. 8. Wall, R. L., Conrad, F. G. Arch. intern. Med. 1961, 108, 456. 9. Warwick, O. H., Sellers, A. H. Canad. med. Ass. J. 1959, 80, 423.
Meanwhile
most therapists follow the kind of scheme by BERSAGEL,1° who uses a clinical classification resembling that of WARWICK and SELLERS. Stage-iI patients are treated with X rays confined to the affected field and adjacent areas, sometimes combined with surgical removal of an accessible mass. Stage-na patients are also given X rays, but the treatment is necessarily more widespread; for stage-lib patients chemotherapy and radiotherapy are combined. In stage-m cases chemotherapy, preferably intravenous nitrogen mustard, is relied on; X rays are used only for resistant local masses. Many workers are impressed, as HANCOCK is, by the value of combined radiotherapy and chemotherapy for
set out
the severer cases. Thus, Roos and VIDEBAEK 11 in Denmark reported a five-year survival of 33% in a group of patients with Hodgkin’s disease on radiotherapy alone, and of 41% in a group on combined treatment. On the other hand RosENBERG et al.12considered that, in the treatment of lymphosarcoma in children, new methods had no advantage over radiotherapy. Clearly, more information from comparable series of cases is
needed.
Annotations POTENCY CONTROL OF SALK VACCINE
ONE of the main disadvantages of the Salk inactivated vaccine has been its relatively poor immunising potency against type-1 poliomyelitis infection, the most serious of the three types. Unfortunately this deficiency was not dealt with when the Salk vaccine was first introduced for general immunisation; for at that time more attention was paid to preparing large quantities of vaccine to meet the heavy demands than to increasing its potency. In recent years, however, work on the development of a more potent Salk vaccine has been intensified and the most encouraging results so far are those reported by Charney and his colleagues.13 They have prepared a highly purified concentrated vaccine, the potency of which greatly exceeds that of vaccine prepared by the usual methods. Tests have shown that two doses of the purified vaccine are able to induce antibody responses to all three types of poliovirus in almost 100% of initially non-immune persons. Although this is a major advance towards a more satisfactory Salk vaccine, there remains the problem of controlling potency in order to ensure that only effective vaccines are released for immunisation of man. An interesting approach to this problem is reported by Dr. Beale on p. 1166 of this issue. He has shown, using a number of different vaccines, that there is a direct correlation between their D-antigen content as measured by an in-vitro agar-gel precipitation test and their ability to induce the production of specific neutralising antibodies in 3-weekBersagel, D. E. in Cancer Chemotherapy (edited by R. L. Clark, Jr.); p. 84 et seq. Springfield, Ill., 1961. 11. Roos, D., Videbaek, A. Danish med. Bull. 1959, 6, 177. 12. Rosenberg, S. A., Diamond, H. D., Craver, L. F. Ann. intern. Med. 1960, 53, 877. 13. Charney, J., Tytell, A. A., Machlowitz, R. A., Hillman, M. R. J. Amer. med. Ass. 1961, 177, 591.
10.
the persistence of cholinergic pathways. The loss of the peristaltic wave presumably results from disappearance of the myenteric ganglia of the body of the oesophagus.
Chemotherapy
explained by
.
How, then, are we to treat this disorder ? There can be no hope of return to normal function, and reduction of the resting tone of the sphincter seems the only possible method. Anticholinergic drugs have not
proved successful, although intravenoushyoscine butylbromide has been claimed to relax the sphincter .12 Dilatation, although easily performed, is unpredictable in its efficacy; only about half to two-thirds of patients obtain reasonable relief for long periods and then often only after several dilatations.13 14 With this procedure the risk of oesophageal rupture is about 2%.13 It cannot be carried out at all when the oesophagus is grossly dilated with sigmoid deformity; and where it can be carried out the greatest disadvantage perhaps is the danger of reducing symptoms to a level at which the patient will accept the disorder, unaware of the insidious progression towards stage 3. BRAIN1 believes that Heller’s cardiomyotomy is the treatment of choice, especially in the earlier stages, since fibrous strictures from foodstagnation oesophagitis and the development of carcinoma seem to be commoner in the large sigmoid oesophagus. BROWSE and CARTER,15 reviewing their experience of the late results of cardiomyotomy in 15 patients followed for from four to twelve years, conclude that Heller’s operation, though useful, achieves little. Only 7 patients were cured of their dysphagia, but 7 more felt it was much improved. 13 had no further regurgitation and felt that on this ground alone the operation was worth while. Pain was relieved by operation in 2 out of 5 cases. Radiological assessment after operation showed that 5 patients had no delay in emptying and no dilatation, while 9 had persistent obstruction and dilatation. No return of peristaltic activity was seen; but in about half the cases the oesophageal dilatation was considerably reduced-which seems to accord with the experience of other workers.16
Perhaps we expect more from cardiomyotomy than it can give. The most important aim of treatment should be to halt progression to stage 3. It seems likely that treatment by administration of nitrites is justifiable only while the patient is waiting for more vigorous treatment; they do not prevent progressive dilatation and are of little help in the earlier stages when the oesophagus can hold only a few ounces. Dilatation of the sphincter may be suitable during stage 1, provided that the extent of cesophageal dilatation is assessed radiologically least once a year; but the advent of stage 2 is an indication for operation,2 13which should never be delayed until stage 3. How many have said after cardiomyotomy, undertaken after temporising treatment with nitrites or dilatations: " Why ever didn’t you operate years ago ?" at
Wright, J. T. Brit. J. Radiol. 1961, 34, 113. Olsen, A. M., Harrington, S. W., Moersch, H. J., Andersen, H. A. J. thorac. Surg. 1951, 22, 164. 14. Lawrance, K., Shoesmith, J. H. Thorax, 1959, 14, 211. 15. Browse, N. L., Carter, S. J. Brit. J. Surg. 1961, 49, 59. 16. Acheson, E. D., Hadley, G. D. Brit. med. J. 1958, i, 549. 12. 13.
or
Radiotherapy
for Reticuloses ? LONG before any effective chemotherapy had been treatment of reticuloses by X rays and radium had become well established. Special hospitals for radiotherapy had been built, and a widespread service for diagnosis and follow-up had been organised. The radiotherapists had collected an impressive body of information about the sensitivity of tumours and reticuloses, the best methods of applying radiotherapy, and the likely survival of the patients. Chemotherapy for tumours and reticuloses is based on the properties of nitrogen mustard, and nearly all the drugs used today For tumours, radioare variations of this molecule. remains the best treatment in nearly all cases. therapy is used for Chemotherapy only palliation of tumours beyond the reach of radiotherapy or in special circumstances ; for instance, CLIFFORD et al.l showed what could be done in malignant disease of the head and neck by a combination of nitrogen-mustard therapy and auto-
introduced, the
logous marrow infusion: they used this method because X-ray therapy is not available in East Africa. In reticuloses, on the other hand, chemotherapy has advantages because the lesions are often multifocal and spread over various areas of the body. Radiotherapy is hardly ever used nowadays in chronic leukaemias: busulphan for chronic myeloid leukaemia, and mustine or chlorambucil for chronic lymphatic leukaemia, are the remedies of choice. But when the management of Hodgkin’s disease and the similar reticuloses is to be decided, the choice between chemotherapy and radiotherapy is much less clear-cut. The subject has been debated by the British Institute of Radiology. HOLME and KUNKLER2 present the case for radiotherapy. They admit that when a reticulosis has become widespread such treatment is no longer worth while; but " where the disease is apparently still localised to one lymph node area or to the site of origin and adjacent nodes, the survival rate following radiotherapy is of the same order as that obtained in carcinomata of accessible sites ". In a series of 48 patients with localised lymphosarcoma, the five-year survival-rate was 44%; for 86 patients with reticulosarcoma the rate was 30%. Adequate treatment has some drawbacks because not only the tumour has to be irradiated: the lymph-nodes draining the affected area and any probable line of extension from the primary area are also included. Thus, the irradiated area may extend " from the base of skull to below the clavicles-and doses of the order of 3,000r in four weeks must be given ". The side-effects of such treatment can include loss of taste and smell, reduction of salivary secretion, radiation caries, radiation myelitis, and late affection of lungs, kidneys, bowels, and bones. Nevertheless, HOLME and KUNKLER believe that the method is justified by the results: the five-year survival figure for lymphosarcoma and reticulosarcoma of the tonsil was 55%, and for similar affections of the cervical nodes 62%. The survival-rate for apparently localised cases of Hodgkin’s disease was 53%, and these workers note that 1. 2.
Clifford, P., Clift, R. A., Duff, J. K. Lancet, 1961, i, 687. Holme, G. M., Kunkler, P. B. Brit. J. Radiol. 1961, 34, 569.
1185
local
is rare so that supplementary chemois therapy unlikely to improve the result: they agree with EDITH PATERSON,3 who found no significant effect on prognosis when mustine was given simultaneously with
clinics where chemotherapy has for some time been given first in preference to radiotherapy: the figures for fouryear survival with proper clinical grading in a series of patients so treated would provide a basis for a proper
X-ray therapy.
comparison.
recurrence
HANCOCK4 states that in his hospital the practice is
to
generalised Hodgkin’s disease first with chemotherapy, using either intravenous mustine or oral chlorambucil or both, which is followed by radiotherapy to any residual masses. He cites the figures published by COOK5 of Michigan, who studied a group of 212 patients; about half of them had high-voltage X-ray therapy alone, and about half had X-ray and nitrogenmustard therapy combined. The five-year survivalrates of the two groups were about equal, but, since treat
of the more advanced cases received combined and the localised cases X-ray alone, COOK considers that combined treatment is the more effective. JELLIFFE and NABARRO6 report their experience with corticosteroids in the treatment of reticuloses. They recommend prednisone in doses of 30 mg. or more daily. On the whole their results were disappointing; but steroids are useful in haemolytic ansemia when this occurs, and in the reduction of gland masses when further radiotherapy or chemotherapy is inadvisable. No paper from this debate gives information about the results of chemotherapy alone. Many such reports have, of course, appeared 7; but it is difficult to compare the reported results of pure chemotherapy and chemotherapy combined with X-ray treatment, for two reasons. The first is that few accounts of chemotherapy give results for four-year or five-year survival, and in many cases the drug on trial has been given to patients who had already received other forms of treatment. For example, WALL and CONRAD s have reported their experience with cyclophosphamide; they treated 29 patients with Hodgkin’s disease, 28 of whom had previously received radiotherapy or chemotherapy or both; none of the patients were followed for more than a year. They reported " good " results in 10 patients on this short-term basis. The second reason is that few reporters give a clinical classification of the severity of their cases. WARWICK and SELLERS9 divided cases into class i (disease limited to a single area), class n (disease involving more than one lymphatic group in a single anatomical area [a] without and [b] with constitutional signs and symptoms), and class III (generalised disease with serious constitutional signs and symptoms). The prognosis, based on four-year survival, is about three times as good for class i as for class III, with class 11 intermediate. Unfortunately, the usual practice, when both forms of treatment are available, is to give radiotherapy to patients in class i and class lia, and to give chemotherapy to the more severely affected patients in classes lib and III. This bias makes objective comparison between the two forms of treatment difficult. There are
most
treatment
3. Paterson, E. Brit. J. Cancer, 1958, 12, 332. 4. Hancock, P. E. T. Brit. J. Radiol. 1961, 34, 573. 5. Cook, J. C. Amer. J. Roentgenol. 1959, 82, 651. 6. Jelliffe, A. M., Nabarro, J. D. N. Brit. J. Radiol. 1961, 34, 577. 7. See Lancet, 1959, i, 1233; ibid. 1961, i, 265. 8. Wall, R. L., Conrad, F. G. Arch. intern. Med. 1961, 108, 456. 9. Warwick, O. H., Sellers, A. H. Canad. med. Ass. J. 1959, 80, 423.
Meanwhile
most therapists follow the kind of scheme by BERSAGEL,1° who uses a clinical classification resembling that of WARWICK and SELLERS. Stage-iI patients are treated with X rays confined to the affected field and adjacent areas, sometimes combined with surgical removal of an accessible mass. Stage-na patients are also given X rays, but the treatment is necessarily more widespread; for stage-lib patients chemotherapy and radiotherapy are combined. In stage-m cases chemotherapy, preferably intravenous nitrogen mustard, is relied on; X rays are used only for resistant local masses. Many workers are impressed, as HANCOCK is, by the value of combined radiotherapy and chemotherapy for
set out
the severer cases. Thus, Roos and VIDEBAEK 11 in Denmark reported a five-year survival of 33% in a group of patients with Hodgkin’s disease on radiotherapy alone, and of 41% in a group on combined treatment. On the other hand RosENBERG et al.12considered that, in the treatment of lymphosarcoma in children, new methods had no advantage over radiotherapy. Clearly, more information from comparable series of cases is
needed.
Annotations POTENCY CONTROL OF SALK VACCINE
ONE of the main disadvantages of the Salk inactivated vaccine has been its relatively poor immunising potency against type-1 poliomyelitis infection, the most serious of the three types. Unfortunately this deficiency was not dealt with when the Salk vaccine was first introduced for general immunisation; for at that time more attention was paid to preparing large quantities of vaccine to meet the heavy demands than to increasing its potency. In recent years, however, work on the development of a more potent Salk vaccine has been intensified and the most encouraging results so far are those reported by Charney and his colleagues.13 They have prepared a highly purified concentrated vaccine, the potency of which greatly exceeds that of vaccine prepared by the usual methods. Tests have shown that two doses of the purified vaccine are able to induce antibody responses to all three types of poliovirus in almost 100% of initially non-immune persons. Although this is a major advance towards a more satisfactory Salk vaccine, there remains the problem of controlling potency in order to ensure that only effective vaccines are released for immunisation of man. An interesting approach to this problem is reported by Dr. Beale on p. 1166 of this issue. He has shown, using a number of different vaccines, that there is a direct correlation between their D-antigen content as measured by an in-vitro agar-gel precipitation test and their ability to induce the production of specific neutralising antibodies in 3-weekBersagel, D. E. in Cancer Chemotherapy (edited by R. L. Clark, Jr.); p. 84 et seq. Springfield, Ill., 1961. 11. Roos, D., Videbaek, A. Danish med. Bull. 1959, 6, 177. 12. Rosenberg, S. A., Diamond, H. D., Craver, L. F. Ann. intern. Med. 1960, 53, 877. 13. Charney, J., Tytell, A. A., Machlowitz, R. A., Hillman, M. R. J. Amer. med. Ass. 1961, 177, 591.
10.